PRACTICE | FIVE THINGS TO KNOW ABOUT ...

Drug interactions with cannabinoids

Tony Antoniou PhD, Jack Bodkin BScPhm, Joanne M.-W. Ho MD MSc

n Cite as: CMAJ 2020 March 2;192:E206. doi: 10.1503/cmaj.191097

1 Cannabinoid levels can be increased by other medications

Delta-9-tetrahydrocannabinol (THC) and cannabidiol are pharmacologically
active cannabinoids in marijuana that are metabolized by cytochrome P450
(CYP)3A4; THC is also metabolized by CYP2C9, a liver enzyme.1 A pharmaco-
kinetic study found that the CYP3A4 inhibitor ketoconazole nearly doubled
THC and cannabidiol concentrations,2 and similar interactions could occur
with other CYP3A4 inhibitors, including macrolides and verapamil, aug-
menting the psychoactive effects of THC and dose-related adverse effects of
cannabidiol (e.g., somnolence, transaminase elevation).1,2 CYP2C9 inhib­
itors such as cotrimoxazole, fluoxetine and amiodarone would also be
expected to increase THC exposure and psychoactive effects.1
References
1. Cox EJ, Maharao N, Patilea-Vrana G, et al. A marijuana-drug
interaction primer: precipitants, pharmacology, and pharma-
cokinetics. Pharmacol Ther 2019;201:25-38.
2. Stott C, White L, Wright S, et al. A Phase I, open-label, ran-
domized, crossover study in three parallel groups to evaluate
the effect of Rifampicin, Ketoconazole, and Omeprazole on
the pharmacokinetics of THC/CBD oromucosal spray in
healthy volunteers. Springerplus 2013;2:236.
3. Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction
between clobazam and cannabidiol in children with refractory
epilepsy. Epilepsia 2015;56:1246-51.
4. Leino AD, Emoto C, Fukuda T, et al. Evidence of a clinically
significant drug-drug interaction between cannabidiol and

2
 Cannabinoids can affect levels of other drugs
5. Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and
Cannabidiol inhibits CYP2C19, increasing levels of the active metabolite of
clobazam threefold.1,3 Interactions with other drugs metabolized by
CYP2C19 (Appendix 1, available at www.cmaj.ca/lookup/suppl/
doi:10.1503/cmaj.191097/-/DC1) should be anticipated. Very high interna-
tional normalized ratio levels and bleeding have been reported with com-
bined used of warfarin and marijuana. 1 A case reporting a threefold
increase in tacrolimus levels following the addition of cannabidiol shows
that CYP3A4/5 inhibition can also occur.4
tacrolimus. Am J Transplant 2019;19:2944-8.
the pharmacodynamics of cannabinoids. Br J Clin Pharmacol
2018;84:2477-82.
Competing interests: None declared.
This article has been peer reviewed.
Affiliations: Department of Family and Community
Medicine (Antoniou), St. Michael’s Hospital and Uni-
versity of Toronto; Li Ka Shing Knowledge Institute

3 Smoking marijuana can increase clearance of some drugs
Smoked marijuana increases the clearance of theophylline 40%.1 Similar find-
ings would be expected for other drugs metabolized by CYP1A2, such as olan-
zapine. Increased drug clearance occurs with regular marijuana use (> 2 mari-
juana cigarettes per week); no effect of occasional use has been reported.
(Antoniou), St. Michael’s Hospital, Toronto, Ont.;
Department of Medicine (Bodkin, Ho), McMaster Uni-
versity, Waterloo, Ont.; Grand River Hospital
­(Bodkin), Kitchener, Ont.; Schlegel Research Institute
for Aging (Ho), Waterloo, Ont.
Correspondence to: Tony Antoniou, Tony.Antoniou​
@unityhealth.to

4 Additive effects can occur with other drugs

Additive effects can occur when marijuana is combined with sympathomi-
metics (e.g., tachycardia, hypertension), central nervous system depressants
such as alcohol and opioids (e.g., drowsiness, ataxia), and anticholinergics
(e.g., tachycardia, confusion).5

5 There are potential “red flag” interactions

Though further research is needed, marijuana may have serious interac-
tions with drugs including warfarin (increased international normalized
ratio and risk of bleeding); clobazam (increased risk of benzodiazepine
toxicity); central nervous sytem depressants and sympathomimetics
(additive effects); and theophylline, clozapine and olanzapine (reduced
efficacy). Patients should be advised about possible increased canna­
binoid effects with concomitant CYP3A4 and 2C9 inhibitors (Appendix 1).1,5
Alternatives that do not interact with marijuana should be selected when
clinically feasible.

E206 CMAJ | MARCH 2, 2020 | VOLUME 192 | ISSUE 9 © 2020 Joule Inc. or its licensors